Chronic postoperative pain: Genetic and Neural Circuit Mechanisms

慢性术后疼痛：遗传和神经回路机制

• 批准号: 10413127
• 负责人: Norman Taylor
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413127
• 关键词: Absence of pain sensation; Acute; Affect; Amputation; Animal Model; Biological Markers; Cardiac Surgery procedures; Catecholamines; Cells; Chronic; Diagnosis; Economics; Exhibits; Exposure to; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomic approach; Goals; Inbred Dahl Rats; Incidence; Methyltransferase Gene; Modeling; Neurons; Nociception; Operative Surgical Procedures; Outcome; Pain; Pain management; Patients; Persistent pain; Persons; Pharmacology; Physiological; Postoperative Pain; Psychological Factors; Public Health; Rattus; Research; Risk; Risk Factors; Role; Serotonin; Spinal Cord; Sprague-Dawley Rats; Stimulus; Testing; Thoracotomy; Variant; breast surgery; chronic pain; congenic; consomic; demographics; diffuse noxious inhibitory control; dopamine system; dopaminergic neuron; efficacious treatment; experience; midbrain central gray substance; multimodality; neural circuit; novel; optogenetics; phenotypic biomarker; prevent; response; surgery outcome

PROJECT SUMMARY Chronic (or persistent) postoperative pain (CPOP) is a potentially devastating outcome from an otherwise successful surgical procedure. It affects millions of patients every year, with pain lasting for months to years, resulting in patient suffering and resulting economic hardship. The surgeries with the highest incidence of chronic postoperative pain are amputations, thoracotomies, cardiac, and breast surgery. Other risk factors include preoperative pain, psychological factors, demographics, and the intensity of acute postoperative pain. Attempts to prevent chronic postoperative pain have largely been unsuccessful, with no change in the incidence despite increased use of regional and multimodal analgesia. Therefore, further research is needed to identify biomarkers to accurately predict those at risk for developing chronic postoperative pain and treatments that reduce the incidence. We hypothesize that Diffuse Noxious Inhibitory Control (DNIC) efficiency is predictive of who will develop chronic postoperative pain. Thus, a better understanding of the mechanisms responsible for DNIC will result in more efficacious treatments. We would expect that patients or animal models with less efficient DNIC would be ‘at risk’ for developing chronic pain when exposed to the painful stimulus of surgery. Our overall objectives in this application are to use a new model of persistent postoperative pain, the Dahl S rat, to investigate the involvement of serotonin, catecholamine and dopamine systems on DNIC using pharmacologic, chemogenetic and optogenetic approaches. We will also investigate which genetic polymorphism(s) are responsible for the persistent postoperative pain experienced by the Dahl S rat. This will be accomplished in three projects. Project 1: will determine the relationship between DNIC and CPOP. DNIC responses will be abolished in Sprague Dawley rats and restored in Dahl S rats, and the resultant effects on postoperative pain persistence ascertained. We will also test the hypothesis that the absent DNIC response in SS rats is a result of increased nociceptive facilitation by serotonergic “on cells” in the rostral ventral medulla by optogenetically inhibiting serotonergic neurons in the spinal cord. Project 2 will examine the role of periaqueductal gray dopamine neurons on DNIC and postoperative pain using a Dahl S rat expressing a novel variant of the Catecholamine-O-methyltransferase gene that increases dopaminergic tone. Project 3 will use a powerful physiologic genomics approach, the use of consomic and congenic rats, to identify the gene polymorphism(s) responsible for the absent DNIC response and persistent postoperative pain exhibited by Dahl S rats. We expect our studies to provide genetic and phenotypic biomarkers to guide diagnosis and treatment decisions in chronic postoperative pain.

项目摘要 慢性（或持续性）术后疼痛（CPOP）是否则可能是毁灭性的结果 成功的手术程序。它每年都会影响数百万患者，疼痛持续数月至数年， 导致患者痛苦和经济困难。慢性事件最高的手术 术后疼痛是截肢，胸痛，心脏和乳房手术。其他风险因素包括 术前疼痛，心理因素，人口统计学和急性后疼痛的强度。尝试 为了防止慢性存在，疼痛在很大程度上没有成功，事件目的地没有变化 区域和多模式镇痛的使用增加。因此，需要进一步的研究来识别生物标志物 准确预测那些患有慢性存在疼痛和治疗的风险的人 发病率。我们假设弥漫性有害抑制控制（DNIC）效率可以预测谁将 发展慢性存在疼痛。这是对负责DNIC的机制的更好理解 导致更有效的治疗。我们希望患者或效率较低的患者模型 当受到手术疼痛刺激时，会出现慢性疼痛的“风险”。我们的整体 本应用程序中的目标是使用持续性术后疼痛的新模型Dahl S Rat进行调查 使用药物学，5-羟色胺，儿茶酚胺和多巴胺系统的参与， 化学发生和光遗传学方法。我们还将研究哪些遗传多态性是 负责达尔（Dahl）大鼠持续的术后疼痛。这将在 三个项目。项目1：将确定DNIC和CPOP之间的关系。 dnic回应将是 在Sprague Dawley大鼠中废除并在Dahl的大鼠中恢复，并对术后疼痛产生影响 持久性确定。我们还将检验以下假设，即SS大鼠缺乏DNIC反应是结果 通过光生的腹腹髓质中血清素能“在细胞上”增加的伤害感受器 抑制脊髓中的血清能神经元。项目2将检查灰灰色的作用 使用DAHL S大鼠表达新型变体的DNIC和术后疼痛的多巴胺神经元 儿茶酚胺-O-甲基转移酶基因增加多巴胺能张力。项目3将使用强大的 生理基因组学方法，一种使用综合大鼠和先天性大鼠的使用，以鉴定基因多态性 负责Dahl S大鼠缺乏DNIC反应和持续的术后疼痛。我们期望 我们的研究提供遗传和表型生物标志物来指导慢性的诊断和治疗决策 术后疼痛。